O13 A case of chronic recurrent multifocal osteomyelitis

Abstract Case report - Introduction We present the case of a young adult female who presented to rheumatology with persistent arthralgia of her knees despite disease-modifying anti-rheumatic drugs (DMARDs) for seronegative inflammatory arthritis. Her magnetic resonance imaging (MRI) of her knees demonstrated bone lesions compatible with chronic recurrent multifocal osteomyelitis (CRMO). CRMO is a rare autoinflammatory condition of the bone, typically affecting younger female patients. It is characterised by the presence of multifocal inflammatory bone lesions, often affecting the metaphyses of long bones. It can present with localised pain and swelling, and such as in this case, joint swelling. Case report - Case description An 18-year-old female patient presented to rheumatology in October 2019 with a 4-week history of left knee monoarthritis. Due to a history of a preceding upper respiratory tract infection, oral non-steroidal anti-inflammatories (NSAIDs) were commenced for possible reactive arthritis. She had no history of seronegative features of psoriasis, uveitis, inflammatory bowel disease, pustulosis or acne. Over the next 4 weeks, she experienced intermittent episodic bilateral knee effusions associated with elevated inflammatory markers. C-reactive protein (CRP) peaked at 232mg/L and erythrocyte sediment rate (ESR) at 57mm/1hr. Rheumatoid factor, anti-cyclic citrullinated peptide (CCP) antibodies and antinuclear antibody (ANA) were negative. Plain X-rays of the knees were normal. MRI of the right knee and hip in October 2019 were reported as normal. An ultrasound scan of the right knee in December 2019 between episodes of swelling, was normal. She continued to experience persistent knee and right hip arthralgia, with stiffness and limitation of knee flexion. DMARD treatment was commenced in December 2019 due to intermittent synovitis of the knees. Inflammation in the knees persisted despite treatment with oral Methotrexate. The additional Sulfasalazine was discontinued due to neutropaenia. Etanercept (Benepali) was commenced in November 2020 with good clinical and biochemical response. However, despite resolution of knee effusions, knee arthralgia persisted with stiffness and limited knee flexion. Repeat MRI imaging revealed multiple areas of hypointense signal surrounding central areas of hyperintense signal. These are characteristic of CRMO. On review of the initial right knee MRI from October 2019, it was noted that subtle lesions were visible. Bone turnover markers were checked; beta-crosslaps was 573ng/L and type 1 procollagen peptide was 59.7ug/L. The patient has now begun a 1-year treatment course of IV pamidronate in addition to continuing her methotrexate and Benepali. Case report - Discussion CRMO is a rare condition, affecting approximately 4 per million. It typically affects children, more commonly females. Although the most common presenting symptoms are pain and local tenderness, patients may also report warmth and localised swelling. Systemic features can occur, albeit rarely. Although it can affect multiple sites, including the spine, the metaphyses of long bones are commonly involved. CRMO is a non-infectious autoinflammatory bone disorder, thought to be due to abnormal production of pro- and anti-inflammatory cytokines, which in turn affect the activation of osteoclasts within bone. Although plain X-rays may be normal, they may show evidence of osteolytic lesions or sclerosis later in the disease process. MRI is the preferred imaging modality and can demonstrate areas of bone marrow oedema and periostitis. The MRIs of this patient showed multiple large geographic lesions bilaterally demonstrating hypointense signal peripherally with central areas of hyperintense (high) signal. Both the epiphyses and metaphyses of the long bones were affected, which is characteristic of CRMO. Similar appearances could be seen in bone infarcts, for example in sickle cell disease; however, these would usually only affect the metaphyses of bone. Although the previous imaging was reported to be unremarkable, some subtle lesions can be seen. This patient’s isotope bone scan revealed non-specific uptake in the knees and shoulders, rather than localised areas of uptake which are typical in CRMO. A bone biopsy can differentiate CRMO from important differentials such as infective osteomyelitis and malignancy. In this patient, a bone biopsy was discussed but not undertaken as there was widespread involvement with no clear satellite lesion. Management of CRMO encompasses a variety of treatments, including NSAIDs, steroids, DMARDs and bisphosphonates largely based upon smaller trials. Due to ongoing symptoms despite conventional synthetic and biologic DMARDs, in this patient IV pamidronate treatment was commenced. Case report - Key learning points This case highlights the importance of considering CRMO in young adult patients with seronegative arthritis who do not respond to standard therapy. There were no identifiable features of bone inflammation on either plain X-rays or knee ultrasound and no reported features on the initial MRI of the right knee. This case reinforces the need for multidisciplinary team discussion with an experienced specialist musculoskeletal radiologist, especially when symptoms are discordant from the clinical examination findings, posing diagnostic uncertainty. In this case, it transpired that evidence of CRMO could be seen on the initial MRI which was taken approximately 18 months before the diagnosis was made. Given that this patient had active bone inflammation despite treatment with conventional synthetic and biologic DMARDs, she was commenced on intravenous bisphosphonates which inhibit osteoclastic activity and can reduce inflammatory cytokine production. Bisphosphonates can cross the placenta and potentially impair normal bone development in utero. This can pose a management challenge in young adult females of child-bearing age. Pamidronate has been shown to be useful in cases of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis); a related condition where non-infectious osteomyelitis is associated with dermatological manifestations of acne and pustulosis. Treatment response can be monitored by clinical improvement and by biochemical markers of bone turnover, such as beta-crosslaps and type 1 procollagen peptide (P1NP). In this case, the patient was found to be vitamin D deplete and required replacement therapy prior to pamidronate therapy. After initiating treatment, bone turnover markers have reduced although arthralgia persists. A 1-year treatment course has been planned with a repeat MRI to reassess radiological response at that time.

The patient was reviewed 4-weeks later at which stage her symptoms had improved. Prednisolone had been stopped a week prior with no deterioration in her joint symptoms. Peripheral blood cultures taken during admission revealed no growth at 5 days. After discharge the results of the molecular PCR testing on the synovial fluid samples became available and were positive for bacterial 16S rDNA. Referral to the Public Health England Meningococcal Reference Unit ensued and further molecular typing confirmed N. meningitidis with capsular genogroup B. Subsequent non-culture sequencing of the factor H binding protein and PorA epitope revealed it to belong to the subtype P 1.12-1,9 and hence the utility of vaccination with Bexsero could not be determined. Case report -Discussion: The patient was unusual in having a primary meningococcal arthritis (PMA), defined as an acute septic arthritis without meningitis. The fever and transient rash may have suggested mild meningococcaemia. Direct bacterial invasion of the synovium via the bloodstream is likely to be the route of spread in our patient. Confirming meningococcal disease used to be very challenging with negative peripheral blood culture results confounded by early antibiotic usage and the presence of fastidious and uncultivable organisms. Culture detection of N. meningitidis is 100% specific but is limited by a sensitivity of around 31%. After parenteral antibiotic administration the isolation rate of N. meningitidis drops from 50% to less than 5%. The development of quantitative PCR (qPCR) has improved detection rates and a positive result is diagnostic. qPCR is a culture-independent assay that can quantify bacterial load, is easy to use and has flexibility in design. The broad coverage of qPCR assay is able to use the 16S rRNA gene as a target and hence the overall result of the assay will be able to give both qualitative and quantitative characterisation. The qPCR is a nucleic acid amplification test and hence doesn't require the presence of viable bacteria for a positive result; and hence the results are not affected by prior antibiotic administration. The sensitivity of PCR has been shown to be higher than blood cultures with values of 47% and 31%, respectively; specificities of PCR have been noted to be above 96%. It has been previously reported that 31% of culture-negative but clinically suspected meningococcal disease cases were subsequently found to be blood PCR-positive. Comparing this with analysis of synovial fluid which has a gram stain sensitivity of between 29% and 50% and a culture sensitivity of up to 76% shows a marked improvement. Case report -Key learning points: Our case highlights the challenges in differentiating septic arthritis from a reactive arthritis in a patient presenting with knee pain, swelling and pyrexia who subsequently had N. meningitidis identified via 16S rDNA PCR testing. Emphasis is placed on recognising polyarticular septic arthritis as a clinical entity with early joint aspiration being the priority of care. Polyarticular septic arthritis accounts for an estimated 15% of all cases of septic arthritis with a mean of three affected joints. Mortality rates in monoarticular septic arthritis have been estimated to be around 11%, rising to 50% for polyarticular disease. In our patient the timeline of events is an important factor. It has been reported that patients with septic arthritis typically have symptoms for less than 2 weeks at presentation, with the characteristic features of hot, swollen, painful and restricted joints whereas a reactive arthritis presents 2 to 4 weeks after the preceding infection. Our patient suffered from a sore throat, presumed streptococcal in origin, 5 days prior to her oligoarticular symptoms, which led to admission. It would also be pertinent to consider the relevance of the sore throat 5 days prior to presentation. It has been suggested that a post-streptococcal reactive arthritis is a distinct clinical entity from other forms of reactive arthritis. The peak incidence, age, pattern of joint involvement, extra-articular manifestations and HLA B27 association have been reported to vary between the aforementioned conditions and no causal role has been found for streptococcal throat infection.
In conclusion, we have described the first case in the literature of N. meningitidis being identified as the causative organism by PCR assay of synovial fluid in a patient with bilateral septic arthritis of the native knee joint.
ORAL Case report -Introduction: Melorheostosis is a very rare benign bone disorder involving sclerosing hyperostosis. The name derives from the Greek terms Melos 'limb', rheos 'flow' and osteon 'bone'. The incidence of melorheostosis is 0.9 cases per million population, and in the majority of cases is diagnosed before the age of 20 years. It presents with pain, deformities, limitations of a range of motion, contractures, muscle atrophy, and limb swelling. We present a case of a 33-year-old lady who was referred with a history of pain and swelling of the right knee. Case report -Case description: This 33-year-old lady of Nigerian origin was referred to the rheumatology department with a 7-year history of fluctuating pain and swelling in the right knee with the possibility of inflammatory arthritis. Prior to this, she had been seen by the local orthopaedic team with subsequent input sought from the regional specialist orthopaedic bone unit in Birmingham. The synovial biopsies did not show any evidence of inflammation or pigmented villo-nodular synovitis (PVNS). Prior to moving to the UK, she had been assessed in Germany and Dubai due to knee pain and swelling with a diagnosis of the unclear bone-related condition and fibromyalgia. Clinically the right knee had a chronic cool swelling with reduced range of movement but no synovitis and no signs of inflammatory arthritis in other joints. There were no features of seronegative inflammatory arthritis or connective tissue diseases. Investigations showed weak positive ANA with normal CRP, bone profile, FBC, urea and electrolytes, with negative rheumatoid factor and anti-CCP antibody. X-ray knee arranged, showed a flowing periosteal thickening medial cortices of the femur and tibia consistent with 'melorheostosis'. MRI right knee also confirmed the same diagnosis. Imaging of the upper limbs, spine and pelvis showed no involvement. Input from the metabolic bone health team was arranged who did not deem bisphosphonates useful in her case. Physiotherapy input was arranged to improve her leg posture and movements along with appropriate patient education and analgesia titration.
Case report -Discussion: We present a rare mimic of inflammatory arthritis. Initially referred by GP to orthopaedic team who considered PVNS which was ruled out by biopsies, then next question was about inflammatory arthritis due to recurrent history of knee pain and swelling which is valid differential for monoarthritis. Rheumatology assessment noted a puffy knee but no effusion to aspirate, x-ray imaging was diagnostic for melorheostosis due to the typical presence of 'dripping wax appearance'. As rheumatologists while assessing joints, genetic and metabolic causes need to be considered besides inflammatory and infective causes. A thorough history remains essential along with interaction with radiology colleagues which is the main learning point.
Case report -Key learning points: 1. Non-inflammatory conditions like melorheostosis can mimic inflammatory arthritis 2. Simple imaging like X-rays and discussion with radiology colleagues are often underrated.

O13 A CASE OF CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS
Jessica M Weightman and Geetha L Janakiraman James Cook University Hospital, Middlesbrough, United Kingdom Case report -Introduction: We present the case of a young adult female who presented to rheumatology with persistent arthralgia of her knees despite disease-modifying anti-rheumatic drugs (DMARDs) for seronegative inflammatory arthritis. Her magnetic resonance imaging (MRI) of her knees demonstrated bone lesions compatible with chronic recurrent multifocal osteomyelitis (CRMO). CRMO is a rare autoinflammatory condition of the bone, typically affecting younger female patients. It is characterised by the presence of multifocal inflammatory bone lesions, often affecting the metaphyses of long bones. It can present with localised pain and swelling, and such as in this case, joint swelling.
Case report -Case description: An 18-year-old female patient presented to rheumatology in October 2019 with a 4-week history of left knee monoarthritis. Due to a history of a preceding upper respiratory tract infection, oral non-steroidal anti-inflammatories (NSAIDs) were commenced for possible reactive arthritis. She had no history of seronegative features of psoriasis, uveitis, inflammatory bowel disease, pustulosis or acne. Over the next 4 weeks, she experienced intermittent episodic bilateral knee effusions associated with elevated inflammatory markers. Creactive protein (CRP) peaked at 232mg/L and erythrocyte sediment rate (ESR) at 57mm/1hr. Rheumatoid factor, anti-cyclic citrullinated peptide (CCP) antibodies and antinuclear antibody (ANA) were negative. Plain X-rays of the knees were normal. MRI of the right knee and hip in October 2019 were reported as normal. An ultrasound scan of the i8 https://academic.oup.com/rheumap right knee in December 2019 between episodes of swelling, was normal. She continued to experience persistent knee and right hip arthralgia, with stiffness and limitation of knee flexion. DMARD treatment was commenced in December 2019 due to intermittent synovitis of the knees. Inflammation in the knees persisted despite treatment with oral Methotrexate. The additional Sulfasalazine was discontinued due to neutropaenia. Etanercept (Benepali) was commenced in November 2020 with good clinical and biochemical response. However, despite resolution of knee effusions, knee arthralgia persisted with stiffness and limited knee flexion. Repeat MRI imaging revealed multiple areas of hypointense signal surrounding central areas of hyperintense signal. These are characteristic of CRMO. On review of the initial right knee MRI from October 2019, it was noted that subtle lesions were visible. Bone turnover markers were checked; beta-crosslaps was 573ng/L and type 1 procollagen peptide was 59.7ug/L. The patient has now begun a 1-year treatment course of IV pamidronate in addition to continuing her methotrexate and Benepali. Case report -Discussion: CRMO is a rare condition, affecting approximately 4 per million. It typically affects children, more commonly females. Although the most common presenting symptoms are pain and local tenderness, patients may also report warmth and localised swelling. Systemic features can occur, albeit rarely. Although it can affect multiple sites, including the spine, the metaphyses of long bones are commonly involved. CRMO is a non-infectious autoinflammatory bone disorder, thought to be due to abnormal production of pro-and anti-inflammatory cytokines, which in turn affect the activation of osteoclasts within bone.
Although plain X-rays may be normal, they may show evidence of osteolytic lesions or sclerosis later in the disease process. MRI is the preferred imaging modality and can demonstrate areas of bone marrow oedema and periostitis. The MRIs of this patient showed multiple large geographic lesions bilaterally demonstrating hypointense signal peripherally with central areas of hyperintense (high) signal. Both the epiphyses and metaphyses of the long bones were affected, which is characteristic of CRMO. Similar appearances could be seen in bone infarcts, for example in sickle cell disease; however, these would usually only affect the metaphyses of bone. Although the previous imaging was reported to be unremarkable, some subtle lesions can be seen. This patient's isotope bone scan revealed non-specific uptake in the knees and shoulders, rather than localised areas of uptake which are typical in CRMO. A bone biopsy can differentiate CRMO from important differentials such as infective osteomyelitis and malignancy. In this patient, a bone biopsy was discussed but not undertaken as there was widespread involvement with no clear satellite lesion. Management of CRMO encompasses a variety of treatments, including NSAIDs, steroids, DMARDs and bisphosphonates largely based upon smaller trials. Due to ongoing symptoms despite conventional synthetic and biologic DMARDs, in this patient IV pamidronate treatment was commenced. Case report -Key learning points: This case highlights the importance of considering CRMO in young adult patients with seronegative arthritis who do not respond to standard therapy. There were no identifiable features of bone inflammation on either plain X-rays or knee ultrasound and no reported features on the initial MRI of the right knee. This case reinforces the need for multidisciplinary team discussion with an experienced specialist musculoskeletal radiologist, especially when symptoms are discordant from the clinical examination findings, posing diagnostic uncertainty. In this case, it transpired that evidence of CRMO could be seen on the initial MRI which was taken approximately 18 months before the diagnosis was made. Given that this patient had active bone inflammation despite treatment with conventional synthetic and biologic DMARDs, she was commenced on intravenous bisphosphonates which inhibit osteoclastic activity and can reduce inflammatory cytokine production. Bisphosphonates can cross the placenta and potentially impair normal bone development in utero. This can pose a management challenge in young adult females of child-bearing age. Pamidronate has been shown to be useful in cases of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis); a related condition where non-infectious osteomyelitis is associated with dermatological manifestations of acne and pustulosis. Treatment response can be monitored by clinical improvement and by biochemical markers of bone turnover, such as beta-crosslaps and type 1 procollagen peptide (P1NP). In this case, the patient was found to be vitamin D deplete and required replacement therapy prior to pamidronate therapy. After initiating treatment, bone turnover markers have reduced although arthralgia persists. A 1-year treatment course has been planned with a repeat MRI to reassess radiological response at that time. Case report -Introduction: Tumor-induced osteomalacia is a rare acquired metabolic bone disorder characterised by isolated renal phosphate wasting due to abnormal tumour production of fibroblast growth factor 23 (FGF23). Bloods show hypophosphatemia. However, given the lack of awareness of this disease, and the non-specific nature of the presenting symptoms, diagnosis is often delayed for years or even missed. With this case report, we want to shed light on this rare bone disorder and highlight the importance of not ignoring a low phosphate level. Case report -Case description: We report the case of a 63-year-old gentleman who presented to us with a history of progressive bone pain, marked muscle weakness and fatigue. He had a persistently raised parathyroid hormone and very high alkaline phosphatase. Calcium was low normal, but vitamin D was normal. Phosphate was noted to be low and had been so since 6 years prior to being referred. X-ray pelvis showed sclerotic-looking iliac bones, but an isotope bone scan showed no evidence of metastatic disease. We referred him to our endocrinology colleagues to investigate for possible primary hyperparathyroidism. However, ultrasound scan of neck